Reduction Of M-component Research Articles

Daratumumab, a CD38 mab, for the treatment of relapsed/refractory multiple myeloma patients: Preliminary efficacy data from a multicenter phase I/II study.

8019 Background: Daratumumab (HuMax-CD38) is a human CD38 monoclonal antibody with broad-spectrum killing activity; it effectively kills CD38-expressing tumor cells via antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and apoptosis. From an ongoing first-in-human (FIH) dose-escalation study (ClinicalTrials.gov CT00574288), it has been shown that daratumumab has an acceptable safety profile (Gimsing: ASH 2011 abstract 1873). The objectives of this FIH study are to establish the safety profile and MTD. In addition efficacy is evaluated. Methods: Pts ≥18 years and previously diagnosed with MM requiring systemic therapy and considered relapsed or refractory (RR) to at least two different prior lines of therapy and not eligible for salvage ASCT were enrolled. The design of this study encompasses an accelerated dose-escalation based on a classical 3+3 design. Daratumumab is administrated over a 9 wk period encompassing 2 pre-doses and 7 full-doses. The doses range from 0.005 mg/kg to 24 mg/kg. The decision to dose escalate is based on recommendation by an external Independent Data Monitoring Committee. Evaluation of efficacy data was according to Rajkumar (Blood 2011;117:4691-5). The results presented in this abstract are based on preliminary data analyzed before database lock. Results: Data from 23 pts including the 4 mg/kg group are collected. Preliminary efficacy evaluation is based on best paraprotein response as reflected by change in serum and/or urine M-component. For groups ≤ 1 mg/kg, 3/17 pts achieved a reduction in serum M-component (12%, 14%, 19%), in the 2 mg/kg group, 1/3 pts had a reduction in urine M-component (55%), and in the 4 mg/kg group, 3/3 pts had a reduction in the serum M-component of 49%, 55, and 64%, respectively. In the 4 mg/kg group a marked reduction in the percentage of plasma cells in the bone marrow was seen in all pts (80%, 89%, and 97%). The toxicity was manageable. Conclusions: Daratumumab treatment resulted in reductions in M-component and bone marrow plasma cells in pts with RR MM. Toxicity has been manageable. Additional data will be presented at the meeting.

Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Bortezomib as Front-Line Therapy in Primary Plasma Cell Leukemia

Plasma cell leukemia (PCL) is an aggressive, rare variant of multiple myeloma (MM), with peculiar clinical and biological characteristics, which represents about 2–4% of all MM. PCL exists in two forms:primary PCL (about 60% of cases) presents “de novo”, without previous evidence of MM;secondary PCL, which accounts for the remaining 40%, consists of a leukemic transformation occurring in about 1% of patients with a previously diagnosed MM.We have recently shown that bortezomib is an effective agent for the treatment of both primary and secondary PCL, mainly in the setting of pre-treated disease (Musto et al, Cancer 2007). In the present study we conducted a multicenter retrospective survey focused on unselected patients with a diagnosis of primary PCL who had received bortezomib exclusively as first line therapy for the treatment of their disease, outside of clinical trials. To-date, 15 patients, diagnosed according to International Myeloma Working Group criteria, have been collected, 12 of whom (seven male and five female, 49 to 77 year-old) have been so far evaluated for response. Circulating plasma cells ranged from 3 to 95 × 10e9/L. Seven patients had an IgG M-component, two had IgA, two light chains, while one patient was not secretory. Five patients had concomitant extramedullary disease. Unfavourable cytogenetic abnormalities were observed in 4 out of 7 patients with available karyotype. Bortezomib was generally given using the standard schedule of 1.3 mg/sqm days 1, 4, 8, 11, with an interval of 10 days between cycles. Minor modifications were performed, according to tolerance. Three patients received dexamethasone (VD), two dexamethasone and thalidomide (VTD), six doxorubicin and dexamethasone (PAD), and one oral melphalan and prednisone (MPV) in combination with bortezomib, for 2–6 cycles. Three patients underwent autologous, two allogeneic and one a sequence of autologous followed by non-myeloablative allogeneic stem cell transplantation after induction therapy. One out of five eligible patients failed to collect peripheral blood stem cells. Grade 3–4 hematological, neurological, infectious and renal toxicities occurred in 6, 2, 1 and 1 patient, respectively. Other toxicities (diarrhoea, nausea, skin rash) never reached grade 3. According to the International Uniform Response Criteria, 4 partial remissions (reduction of M-component > 50%), 5 very good partial remissions (reduction of M-component > 90%, with positive immunofixation), and 3 complete remissions (negative immunofixation) were achieved (100% overall response). In all patients circulating plasma cells disappeared. One patient with pre-existing renal damage died of progressive disease after 3 months, developing more severe renal failure. Another patient died in CR 6 months after diagnosis, while performing allogeneic stem cell transplantation. Three patients relapsed after 5–8 months and 2 of them died with progressive disease within 4 months from relapse. The remaining 8 patients are alive, and 6 of them maintain their remission phase after 9 to 19 months. One-year progression-free survival and overall survival were 50% and 66.6%, respectively. Primary PCL is usually characterized by poor prognosis. Global response rate to standard chemotherapy is less than 50% and median survival is only 7 months. Stem cell transplantation may be more effective in some, but not all cases. Our findings suggest that, in these patients, the front-line use of bortezomib induces a very high rate of good quality responses, whose duration, however, may be short. This suggests that, in primary PCL, bortezomib should be integrated within more intensive therapeutic programs, including other active drugs and, when possible, stem cell transplantation.

Bortezomib and Plasma Cell Leukemia.

Bortezomib (Velcade) is currently approved in USA and EU for the treatment of resistant/relapsed multiple mieloma (MM). Some reports have suggested that bortezomib is particularly effective for the treatment of extramedullary MM. However, there are very few data about the efficacy of this drug in plasma cell leukemia (PCL), a MM variant usually characterized by very poor prognosis.We retrospectively evaluated 9 patients with PCL diagnosed between October, 2002, and May, 2006, who had received bortezomib for the treatment of their disease (6 males, 3 females; median age 63 years, range 55–74). Six patients had primary and 3 secondary PCL. Eight patients had previously received 1 to 4 lines of chemotherapy, including autologous transplantation (5) and thalidomide (4). One patient was treated at diagnosis. Circulating plasma cells ranged from 2 to 71 x 10e9/L. Median WBC count was 23 x 10e9/L (range 8.1–113). Two patients had a moderate degree of renal failure, 3 had extramedullary disease (jaw, liver, soft tissues). Del 13 was observed in 4 out of 5 patients with available karyotype.Bortezomib was given using the standard schedule of 1.3 mg/sqm days 1, 4, 8, 11, with an interval of 10 days between cycles. Two patients received dexamethasone and thalidomide, 1 thalidomide alone and 3 doxorubicin and dexamethasone in combination with bortezomib. A median of 4 cycles was administered (range 2–6). Grade 3–4 hematological toxicity occurred in 7 patients, while neurological grade 3 toxicity was observed in a single patient. Infections (grade 3) occurred in 4 patients. Other toxicities (diarrhoea, nausea, skin rash) never reached grade 3. Three patients required red cell and/or platelet support. In 3 subjects a reduction of bortezomib dose was required due to hematological or neurological toxicity.Four partial remissions (reduction of M-component > 50%), 3 near-complete remissions (disappearance of M-component at electrophoresis, but positive immunofixation) and 2 complete remissions (negative immunofixation) were achieved (100% overall response), whose duration ranged from 2 to 14 months. In 4 patients autologous transplant procedures were started after response induced by bortezomib. Eight patients are currently alive 7–45 months after diagnosis of PCL. One patient, who had interrupted the treatment after 2 cycles due to herpes zoster, died of progressive disease 7 months later.Our data indicate that bortezomib is very effective in inducing significant responses in patients with primary or secondary PCL and that this drug should be considered for the initial treatment of this disease. Curiously, during the review work, we recorded 3 cases of PCL developed in MM patients under salvage therapies including bortezomib. This intriguing finding, which strongly contrasts with the very good results obtained in patients with previously established PCL, would warrant to be further investigated with “ad hoc” studies.

Bortezomib (Velcade) for progressive myeloma after autologous stem cell transplantation and thalidomide

Twenty-one patients with multiple myeloma, all relapsed after frontline autologous stem cell transplantation and all relapsed again after or resistant to thalidomide (employed as second line treatment) received bortezomib (1.3mg/m2 body surface twice weekly for 2 weeks followed by an interval of 10–12 days) without adjunct of steroids as third line therapy. Three patients died of progressive disease during the first 2 cycles with bortezomib. Eighteen patients received at least 2 cycles and were evaluated for response. According to EBMT criteria, two complete (negative immunofixation) and seven partial (reduction of M-component > 50–75%) remissions were achieved (ITT response rate 42.8%). Duration of response lasted from 2 to 14+ months. Grades 3–4 toxicities (thrombocytopenia, leucopenia, peripheral neuropathy and vasculitis) were observed in seven patients, but no patient interrupted the treatment due to side effects. We conclude that bortezomib alone may induce high quality responses as third line salvage therapy with acceptable toxicity in a significant proportion of homogeneously pre-treated myeloma patients with progressive disease after autologous transplantation and thalidomide.

Possible Multiple Myeloma Dedifferentiation Following Thalidomide Therapy: A Report of Four Cases

Thalidomide has been shown to be effective in approximately 30% of patients with refractory or advanced multiple myeloma (MM). Here we report on 4 cases of patients treated with thalidomide for refractory MM showing dedifferentiation of the neoplasm. In these cases thalidomide treatment—despite reduction of M-component—was followed by disease progression and a very poor clinical outcome which was paralleled by bone marrow plasmacytosis showing marked signs of dedifferentiation, inducing us to speculate on a potential role of thalidomide on dedifferentiation of myeloma cells. In our opinion, a possible dedifferentiation of MM should therefore be taken into account in MM patients treated with thalidomide when clinical course deteriorates despite reduction of M-component.